1,6-naphthyridine derivatives useful for treating diseases of the blood vessels

ABSTRACT

The present invention describes 1,6-naphthyridine derivatives of the general formula: ##STR1## wherein R 1  is an unsubstituted or substituted aromatic or heteroaromatic ring, R 2  is a straight-chained or branched alkyl radical containing up to four carbon atoms or a benzyl radical, R 3  is a hydrogen atom, a straight-chained or branched alkyl radicals or an alkoxycarbonyl radical containing up to four carbon atoms, R 4  is a straight-chained or branched alkyl radical containing up to four carbons and R 5  is a carboxyl group or a straight-chained, branched or cyclic alkoxycarbonyl radical which contains up to 17 carbon atoms and optionally also contains an oxygen, sulphur or nitrogen atom; as well as the pharmacologically acceptable salts thereof, which are useful for treating diseases of the blood vessels.

This is a continuation-in-part of U.S. Ser. No. 891,712 filed July 30,1986 now U.S. Pat. No. 4,711,901 which is a continuation-in-part of U.S.Ser. No. 767,989 filed Aug. 21, 1985, now abandoned.

SUMMARY OF THE INVENTION

The present invention is concerned with new 1,6-naphthyridinederivatives, with the preparation thereof and with pharmaceuticalcompositions containing them.

The new 1,6-naphthyridine derivatives according to the present inventionare compounds of the general formula: ##STR2## wherein R¹ is anunsubstituted or substituted aromatic or heteroaromatic ring, R² is astraight-chained or branched alkyl radical containing up to four carbonatoms or a benzyl radical, R³ is hydrogen atom, a straight-chained orbranched alkyl radical or an alkoxycarbonyl radical containing up tofive carbon atoms, R⁴ is a straight-chained or branched alkyl radicalcontaining up to four carbons and R⁵ is a carboxyl group or astraight-chained, branched or cyclic alkoxycarbonyl radical whichcontains up to 17 carbon atoms and which chain may be interrupted byoxygen, sulphur or nitrogen atom; as well as the pharmacologicallyacceptable salts thereof.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As aromatic or heteroaromatic rings R¹, there are preferred phenyl,thienyl, pyridyl, or 2,1,3-benzoxadiazolyl radicals which areunsubstituted or substituted once or twice by lower polar or non-polarradicals.

1,6-Naphthyridine derivatives of general formula (I) are preferred inwhich R¹ is a phenyl radical mono- or disubstituted by halogen, cyano,nitro, lower alkyl, lower alkoxy, difluoromethoxy, trifluoromethoxy,lower alkylenedioxy, such as methylenedioxy, lower alkylamino,especially dimethyl- or diethylamino, methylthio, difluoromethylthio, ortrifluoromethyl radicals, or is a thienyl, pyridyl or2,1,3-benzoxadiazolyl radical, R³ is preferably a hydrogen atom, analkyl radical containing up to four carbon atoms or an alkoxycarbonylradical containing up to five carbon atoms, R⁴ is preferably an alkylradical containing up to three carbon atoms and especially a methyl orethyl radical and R⁵ is preferably a carboxyl group or an alkoxycarbonylradical containing up to 17 carbon atoms. Complex or voluminous radicalscan here be present which possibly contain further heteroatoms, such asoxygen, sulphur or nitrogen atoms. Typical examples of such radicalsinclude amines, such as lower N-benzyl-N-alkylaminoalkyl radicals,N,N-dialkylaminoalkyl radicals or lower alkylthioalkyl of alkoxyalkylradicals.

Unless otherwise specified, lower "alk" refers to a carbon chain,straight or branched, having up to six carbon atoms.

Especially preferred at 1,6-naphthyridine derivatives of general formula(I) in which R¹ is a phenyl radical optionally substituted preferably inthe 2- or 3-position by halogen, cyano, nitro, methyl, methoxy,difluoromethoxy or trifluoromethyl or is a phenyl radical preferablysubstituted in the 2,3- or 2,6-position by halogen atoms, which can bethe same or different, or is an unsubstituted thienyl radical, R² is amethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl orbenzyl radical, R³ is a hydrogen atom, preferably a methyl but also anethyl or isopropyl radical or an alkoxycarbonyl radical of the generalformula:

    --CO.sub.2 R.sup.6                                         (II)

in which R⁶ is a methyl, ethyl, propyl or isopropyl radical andespecially an ethyl radical, R⁴ is a methyl or ethyl radical and R⁵ is acarboxy group or an alkoxycarbonyl radical of the general formula:

    --CO.sub.2 R.sup.7                                         (III)

in which R⁷ is a hydrogen atom, a methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert-butyl or benzyl radical, an alkoxyalkyl oralkylthioalkyl radical of the general formula:

    --(CH.sub.2).sub.n --O--R.sup.8                            (IV)

or

    --(CH.sub.2).sub.n --S--R.sup.8                            (V)

in which R⁸ is an alkyl radical containing up to three carbon atoms andn is two or three, or an aminoalkyl radical of the general formula:##STR3## in which R⁹ and R¹⁰ can be the same or different and arehydrogen atoms, straight-chained or branched alkyl radicals containingup to four carbon atoms or benzyl radicals or together form a loweralkylene radical containing four to six carbon atoms and n is two orthree.

The present invention also provides a process for the preparation of1,6-naphthyridine derivatives of general formula (I), wherein1,6-naphthyridinone derivatives of the general formula: ##STR4## inwhich R¹, R³, and R⁴ have the same meanings as above and R^(5') is analkoxycarbonyl radical of general formula (III), are alkylated in knownmanner.

Compounds of general formula (I), in which R⁵ is a carboxyl group, arepreferably prepared from compounds of general formula (I), in which R⁵is a benzyloxycarbonyl radical, by hydrogenolytic fission in knownmanner.

The compounds of general formula (VII) can be prepared, for example, inthe manner described in Federal Republic of Germany Patent ApplicationNumber P 33 27 650, in that either

(a) a dihydropyridine of the general formula: ##STR5## in which R¹, R³,R⁴, and R^(5') have the same meanings as above, is reacted withs-triazine in the presence of a base,

(b) a 1,4-dihydropyridine of general formula (VIII) is reacted with adialkylformamide dialkyl acetal of the general formula: ##STR6## inwhich the R¹² substituents can be the same or different and are methylor ethyl radicals and each of the R¹¹ substituents is an alkyl radicalcontaining up to four carbons or the two R¹¹ substituents togetherrepresent an alkylene radical containing up to three carbon atoms, andthe compound obtained of the general formula: ##STR7## in which R¹, R³,R⁴, R^(5'), and R¹² have the same meanings as above, is reacted withammonia, or (c) 2,4-dihydroxypyridine is reacted with a compound of thegeneral formula: ##STR8## in which R¹ and R^(5') have the same meaningsas above and R^(4') is a straight-chained or branched alkyl radicalcontaining up to four carbon atoms, in the presence of ammonia.

The compounds of general formula (XI) are known or can be prepared byprocesses known from the literature (see. Org. Reactions, 15, 204 etseq., 1967). 2,4-Dihydroxypyridine is commercially available.

The 1,4-dihydropyridines of general formula (VIII) used for processes(a) and (b) are known (cf., for example, Chem. Rev., 82, 223, 1982) orcan be prepaed in an analogous manner.

For carrying out process (a), the 1,4-dihydropyridine derivative isheated with s-triazine in an inert organic solvent in the presence of astrong base, for example an alkali metal alcoholate or sodium hydride,to a temperature of from 50° to 160° C. and preferably of from 100° to150° C. As solvents, there are here especially preferred polar solvents,such as dimethyl sulphoxide, dimethylformamide, ethylene glycol dimethylether or lower alcohols, such as ethanol.

For carrying out the reaction according to process variant (b), theappropriate 1,4-dihydropyridine derivative is reacted with an equivalentor excess amount of dialkyl formamide dialkyl acetal, preferably in thepresence of an aprotic solvent, such as dimethylformamide, dimethylsulphoxide or hexamethylphosphoric acid triamide, while heating.Especially preferred formamide acetals include dimethylformamidedimethyl acetal and dimethylformamide diethyl acetal.

The intermediate of general formula (X) obtained according to processvariant (b) is converted into a compound of general formula (VII) byreaction with ammonia in the presence of a preferably aprotic solvent atambient temperature or at an elevated temperature, preferably at theboiling point of the solvent used. As solvents, there are especiallypreferred lower alcohols, such as methanol or ethanol.

Reaction (c) is preferably carried out in inert organic solvents,especially lower alcohols, such as methanol, ethanol or isopropanol. Itis also expedient to work at elevated temperatures, preferably at theboiling temperature of the solvent used. The reaction products can beisolated and purified by known separation processes, such ascrystallization and/or chromatography.

The preparation of the 1,6-naphthyridine derivatives of general formula(I) takes place, according to the present invention, according toconventional processes described in the literature for the O-alkylationof lactams (cf. Adv. Heterocyclic Chem., 12, 185-212, 1970). Appropriatealkylation agents include alkyl halides and alkyl sulphonates, dialkylsulphates and trialkyloxonium salts.

For the reaction with alkyl halides, the compounds of general formula(VII) are used in the form of their metal salts, preferably of theiralkali metal or silver salts, which are either prepared separately orare produced in situ with the help of appropriate bases, such as metalhydrides, carbonates or alkoxides in aprotic solvents.

As appropriate solvents, depending upon the alkylation agent used, therecan be used practically all inert organic solvents, such asopen-chained, cyclic or also aromatic hydrocarbons, for examplen-pentane, n-hexane, cyclohexane, benzene or toluene, halogenatedhydrocarbons, such as dichloromethane or 1,2-dichloroethane, ethers,such as diethyl ether or 1,2-dimethoxyethane, as well as dipolar aproticsolvents, such as dimethylformamide, hexamethylphosphoric acid triamideand dimethyl sulphoxide. Depending upon the solvent used, thetemperature range can be varied between -20° C. and the boiling point ofthe solvent in question.

Because of the ambident character of the lactam anion, in the case ofthe alkylation there are frequently obtained mixtures of O- andN-alkylation products, depending upon the reaction conditions and thealkylation agent used (see. J. Org. Chem., 32, 4040 et seq., 1967). Theproduct mixtures obtained may be separated by chromatographic methodsand/or by crystallization.

The 1,6-naphthyridine derivatives of general formua (I) in which R² is amethyl or ethyl radical are preferably obtained by reaction of the1,6-naphthyridinones of general formula (VII) with trimethyl ortriethyloxonium salts, especially trimethyloxonium tetrafluoroborate, inan aprotic solvent. The preparation of the O-propyl, O-isopropyl,O-butyl, O-sec-butyl, O-isobutyl and O-benzyl compounds, on the otherhand, is preferably carried out by alkylation of the alkali metal saltswith appropriate alkyl- or benzyl halides.

Acidic or basic compounds of general formula (I), in which R⁵ is acarboxyl group or an unsubstituted or substituted aminoalkoxycarbonylradical, are, for the purpose of purification and for galenical reasons,preferably converted into crystalline, pharmacologically acceptablesalts.

When R⁵ is a carboxyl group, with the use of bases, for examplehydroxides or carbonates, there can be prepared the corresponding saltsof the alkali metals or alkaline earth metals. When the substituents R⁴and/or R⁵ have a basic character, salts are obtained in conventionalmanner by neutralization of the bases with appropriate inorganic ororganic acids. As acids, there can be used, for example, hydrochloricacid, sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid,tartaric acid, lactic acid, citric acid, malic acid, salicylic acid,ascorbic acid, malonic acid, or succinic acid.

Since the compounds of general formula (I) according to the presentinvention have a chiral center on C4, they can be present either asracemic mixtures or in the form of the enantiomers.

The compounds of general formula (I) are highly effective calciumantagonists. In contradistinction to known calcium antagonists, attherapeutic concentrations a cardiodepression (negative inotropic,negative chronotropic action is not to be expected.

On the basis of their blood vessel spasmolytic actions, they areespecially indicated in the case of cerebral, cardial, and peripheralblood vessel diseases, such as myocardial ischaemia, cerebral infarct,pulmonary thromboses and arteriosclerosis and other stenoticindications, especially because, in comparison with known compounds witha similar mode of action, negative inotropic side effects aresubstantially absent. Therefore, the 1,6-naphthyridine derivatives ofthe present invention are valuable agents for combatingheart-circulation mortality.

Consequently, a further subject of the present invention is the use of1,6-naphthyridine derivatives of general formula (I) for combating bloodvessel diseases.

The compounds of general formula (I) according to the present inventioncan be administered orally or parenterally in liquid or solid form. Asinjection solution, water is preferably used which contains theadditives usual in the case of injection solution, such as stabilizingagents, solubilizing agents or buffers.

Additives of this kind include, for example, tartrate and citratebuffers, ethanol, complex formers (such as ethylenediamine-tetraaceticacid and the nontoxic salts thereof), as well as high molecular weightpolymers (such as liquid polyethylene oxide) for viscosity regulation.Solid carrier materials include, for example, starch, lactose, mannitol,methyl cellulose, talc, highly dispersed silicic acids, high molecularweight fatty acids (such as stearic acid), gelatine, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats and solid highmolecular weight polymers (such as polyethylene glycols). Compositionssuitable for oral administration can, if desired, also contain flavoringand/or sweetening agents.

Individual dosages to be administered enterally are in the range of fromabout 5 to 250 mg and preferably from 20 to 100 mg. Parenterally, about1 to 20 mg are administered.

The following examples are given for the purpose of illustrating thepresent invention.

EXAMPLE 1 Methyl(±)-4-(2-fluorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate

1.1 g (37 mMol) sodium hydride (80% in paraffin oil) are suspended in 70ml dry dimethylformamide and a solution of 10 g (32 mMol) methyl(±)-4-(2-fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylatein 100 ml dimethylformamide is added dropwise thereto at ambienttemperature, while stirring. After cessation of the evolution of gas,the reaction mixture is further stirred for 30 minutes at ambienttemperature. 5.9 g (35 mMol) isopropyl iodide in 30 ml dimethylformamideare then added. Stirring is continued for 20 minutes at ambienttemperature, then solvent is evaporated off in a rotary evaporator andthe oily residue is stirred with 100 ml water. The resulting pale browncrystalline mass is filtered off with suction, washed with water anddried.

For purification of the crude product, it is crystallized from a mixtureof 400 ml ethyl acetate and 50 ml methanol, the O-alkylation productremaining in highly enriched form in the mother liquor as a readilysoluble component. This is first chromatographed over silica gel withdichloromethane/methanol (9:1 v/v), starting material still presentthereby being completely separated. Further chromatography over silicagel with toluene/ethyl acetate (3:1 v/v) gives almost pure methyl(±)-4-(2-fluorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(R_(f) =0.3). Finally, crystallization from n-hexane/diisopropyl ethergives TLC-pure crystals; m.p. 164°-165° C.

The methyl(±)-4-(2-fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylateused as starting material is prepared as follows:

A solution of 31.5 g (120 mMol) dimethyl4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate in260 ml dimethylformamide is added dropwise, under an atmosphere ofnitrogen, to a suspension of 3.8 g (130 mMol) sodium hydride (80% inparaffin oil) in 60 ml dry dimethylformamide. Upon slowing down of theevolution of gas, the reaction mixture is further stirred for tenminutes at ambient temperature and subsequently 10.0 g (120 mMol)s-triazine in 260 ml dimethylformamide are added dropwise thereto. Thereaction mixture is heated to 110° C. for 16 hours and, after cooling,evaporated in a vacuum. The dark residue is stirred with 600 ml acetone,filtered and the filtrate evaporated in a vacuum. The crude product isboiled with 300 ml methanol, the crystals formed after cooling arefiltered off and, for further purification, are recrystallized frommethanol. There is obtained methyl(±)-4-(2-fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylatein the form of pale beige crystals; m.p. 315°-316° C. (decomp.).

The following compounds are obtained in an analogous manner:

methyl(±)-4-(2-bromoethyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.a); mp 201°-202° C., recrystallized from diisopropyl ether

methyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.b); mp 170° C., recrystallized from diisopropyl ether/methanol

methyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-phenyl-1,6-naphthyridine-3-carboxylate(1.c); mp 132°-133° C., recrystallized from n-hexane

methyl(±)-4-(3-chloro-2-fluorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.d); mp 166°-167° C., recrystallized from n-hexane

methyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.e); mp 174°-175° C., recrystallized from n-hexane

methyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.f); mp 199°-200° C., recrystallized from diisopropyl ether

methyl(±)-4-(2-chloro-6-fluorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.g); mp 194°-195° C., recrystallized from diisopropyl ether

methyl(±)-1,4-dihydro-2-methyl-5-propoxy-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.h); mp 151°-152° C., recrystallized from n-hexane/diisopropyl ether

methyl(±)-4-(2-bromophenyl)-5-ethoxy-1,4-dihydro-2-methyl-1,6-naphthyridine-3-carboxylate(1.i); mp 203°-204° C., recrystallized from toluol/ethyl acetate

ethyl(±)-5-butoxy-1,4-dihydro-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.j); mp 107°-109° C., recrystallized from n-hexane

2-methoxyethyl (±)-1,4-dihydro-5-isopropoxy-2-methyl4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate (1.k); mp 174°-175°C., recrystallized from diisopropyl ether

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.l); mp 102°-103° C., recrystallized from n-hexane

isopropyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.m); mp 111°-112° C., recrystallized from n-hexane

isobutyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.n); mp 115°-116° C., recrystallized from n-hexane

ethyl(±)-4-(2,3-dichlorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-napthyridine-3-carboxylate(1.o); mp 272°-273° C., recrystallized from diisopropyl ether

ethyl(±)-5-sec-butoxy-1,4-dihydro-2-methyl-4-(2-trifluoromethylphenyl)-1,6-napthyridine-3-carboxylatehydrochloride (1.p); mp 148°-150° C., recrystallized from diisopropylether/ethyl acetate

ethyl(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.q); mp 118°-119° C., recrystallized from petroleum ether (bp 60°-80°C.)

tert-butyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.r); mp 209° C. recrystallized from n-hexane/diisopropyl ether

ethyl(±)-2-ethyl-1,4-dihydro-5-isopropoxy-8-methyl-4-phenyl-1,6-naphthyridine-3-carboxylate(1.s); mp 176°-177° C., recrystallized from n-hexane/diisopropyl ether

2-(N-benzyl-N-methylamino)-ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylatedihydrochloride (1.t); mp 148°-150° C., recrystallized from ethylacetate/acetonitrile

2-dimethylaminoethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylatedihydrochloride (1.u); mp 148°-150° C., recrystallized from diisopropylether

2-methylthio-ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.v); mp 154°-155° C., recrystallized from diisopropyl ether/ethylacetate

2-(N-benzyl-N-methylamino)-ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylatedihydrochloride (1.w); mp 163°-165° C. (decomp.), recrystallized fromacetonitrile

diethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3,8-dicarboxylate(1.x); mp 140°-141° C., recrystallized from n-hexane

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylatehydrochloride (1.y); mp 137° C., recrystallized from ethyl acetate

ethyl(±)-1,4-dihydro-5-isopropoxy-4-(2-methoxyphenyl)-2-methyl-1,6-naphthyridine-3-carboxylate(1.z); mp 145°-146° C., recrystallized from n-hexane/diisopropyl ether

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-thienyl)-1,6-naphthyridine-3-carboxylate(1.aa); mp 110°-111° C., recrystallized from n-hexane

ethyl(±)-4-(2-cyanophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.ab); mp 182°-183° C., recrystallized from n-hexane/diisopropyl ether

ethyl(±)-5-benzyloxy-1,4-dihydro-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.ac); mp 142°-143° C., recrystallized from n-hexane/diisopropyl ether

ethyl(±)-2-ethyl-1,4-dihydro-5-isopropoxy-8-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.ad); mp 112°-113° C., recrystallized from n-hexane

benzyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.ae); mp 126°-127° C., recrystallized from n-hexane

2-dimethylaminoethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.af); mp 104°-105° C., recrystallized from n-hexane

3-dimethylaminopropyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.ag); mp 134°-136° C., recrystallized from n-hexane/diisopropyl ether

ethyl(±)-4-(2-difluoromethoxyphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.ah); mp 145°-147° C., recrystallized from n-hexane/diisopropyl ether

2-dibenzylaminoethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.ai); mp 131°-132° C., recrystallized as the sesquiphosphate fromisopropanol

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-methylphenyl)-1,6-naphthyridine-3-carboxylate(1.aj); mp 122°-124° C., recrystallized from n-hexane/diisopropyl ether

2-dimethylaminoethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.ak); mp 91°-93° C., recrystallized from n-hexane/diisopropyl ether

(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-(2-aminoethyl) ester (1.al); mp 166°-167° C. from diisopropylether/ethyl acetate

(±)-4-(2-difluoromethylthiophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylicacid ethyl ester (1.am); mp 124°-125° C. from n-hexane/diisopropyl ether

(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2,3-methylenedioxyphenyl)-1,6-naphthyridine-3-carboxylicacid ethyl ester (1.an); mp 156°-158° C. from diisopropyl ether/ethylacetate

(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-(2-piperidinoethyl) ester (1.ao); mp 118°-120° C. from n-hexane

(±)-4-(2-chlorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylicacid ethyl ester (1.ap); mp 135°-136° C. from n-hexane

(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-phenyl-1,6-naphthyridine-3-carboxylicacid ethyl ester (1.aq); mp 136°-137° C. from n-hexane

(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-[3-(N-benzyl-N-methylamino)propyl]ester.dihydrochloride (1.ar); mp143°-144° C. from dioxane/acetonitrile

(4RS)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-(R)-2-butylester (1.as); mp 100° C. from n-hexane

(4RS)-5-[(RS)-sec-butoxy]-1,4-dihydro-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-[2-N-benzyl-N-methylamino)ethyl]ester.dihydrochloride (1.at); mp149°-152° C. from acetonitrile

ethyl(±)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.au); mp 134°-136° C. from n-hexane

N-benzyl-3-piperidinyl-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.av); mp 205°-207° C. from diisopropyl ether/ethyl acetate

N-benzyl-4-piperidinyl-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.sesquiphosphate(1.aw); mp 147°-148° C. from isopropanol

[2-(N,N-dibenzylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.sesquiphosphate(1.ax); mp 132°-133° C. from isopropanol

[2-(N-methyl-N-phenylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.ay); mp 114°-116° C. from n-hexane/diisopropyl ether

ethyl(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.az); mp 173°-175° C. from n-hexane/diisopropyl ether

[2-(N,N-diethylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.hydrochloride(1.ba); mp 198°-200° C. from isopropanol

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bb); mp 130°-131° C. from n-hexane

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(4-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bc); mp 117°-120° C. from n-hexane

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-pyridyl)-1,6-naphthyridine-3-carboxylate(1.bd); mp 191°-193° C. from cyclohexane/ethyl acetate

ethyl(±)-1,4-dihydro-5-ethoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.be); mp 91°-94° C. from n-hexane

ethyl(±)-1,4-dihydro-2-methyl-5-propoxy-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bf); mp 115°-117° C. from n-hexane

[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate.dihydrochloride(1.bg); mp>165° C. (decomp.) from isopropanol

[2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.dihydrochloride(1.bh); mp 148°-150° C. from acetonitrile

[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-cyanophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.bi); mp 120°-122° C. from diisopropyl ether/ethyl acetate

(2-phenoxyethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.sesquioxalate(1.bj); mp 110°-113° C. from diisopropyl ether

[2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-methoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.sesquioxalate(1.bk); mp 144°-146° C. (decomp.) from ethyl acetate/isopropanol

methyl(±)-4-(2,6-dichlorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.bl); mp 245° C. from diisopropyl ether/ethyl acetate

(2-phenoxyethyl)-(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.hydrobromide(1.bm); mp 108°-109° C. from ether

(2-phenoxyethyl)-4-(2-difluoromethoxyphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate(1.bn); mp 122°-124° C. from diisopropyl ether

benzyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.bo); mp 158°-160° C. from ethanol

cyclopropylmethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bp); mp 112°-114° C. from n-hexane

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.bq); mp 180°-182° from n-hexane/ethyl acetate

(trans-cinnamyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.sesquioxalate(1.br); mp 164°-166° C. from ethyl acetate

[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isobutoxy-2-methyl-1,6-naphthyridine-3-carboxylate.dihydrochloride(1.bs); mp>140° C. (decomp.) from diisopropyl ether/acetonitrile

(N-benzyl-3-pyrrolidinylmethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(1.bt); mp 125°-128° C. from diisopropyl ether

ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bu); mp 130°-131° C. from n-hexane

ethyl(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(1.bv); mp 130°-131° C. from n-hexane

[2-(N-benzyl-N-methylamino)ethyl]-(+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.dihydrochloride(1.bw); mp>137° C. (decomp.) from ether

[2-(N-benzyl-N-methylamino)ethty]-(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate.dihydrochloride(1.bx); mp>136° C. (decomp.) from ether

(2-trimethylammonioethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylateiodide (1.by); mp 149°-150° C. from ethanol

EXAMPLE 2 Methyl(±)-1,4-dihydro-5-methoxy-2-methyl-4-phenyl-1,6-naphthyridine-3-carboxylate

Five g (17 mMol) methyl(±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-phenyl-1,6-naphthyridine-3-carboxylateand 5 g (34 mMol) trimethyloxonium tetrafluoroborate in 200 ml1,2-dichloroethane are stirred for 1.5 hours at ambient temperatureunder an atmosphere of nitrogen. The reaction mixture is shaken out with50 ml water and the organic phase is separated off and evaporated on arotary evaporator. After recrystallization of the residue fromisopropanol, there is obtained the tetrafluoroborate of the desiredcompound. This is stirred with a saturated aqueous solution of potassiumhydrogen carbonate and diethyl ether and the ethereal solution isseparated off, dried over anhydrous sodium sulphate and evaporated on arotary evaporator. Crystallization of the free base from 50 mln-hexane/diisopropyl ether (2:1 v/v) gives colorless crystals; mp210°-212° C.

The methyl(±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-phenyl-1,6-naphthyridine-3-carboxylateused as starting material is prepared analogously to Example 1 with theuse of methyl1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate.

The following compounds are obtained in an analogous manner:

ethyl(±)-4-(2-chlorophenyl)-1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carboxylate(2.a); mp 173°-174° C., recrystallized from n-hexane/diisopropyl ether

ethyl(±)-1,4-dihydro-5-methoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate(2.b); mp 184°-186° C., recrystallized from diisopropyl ether/ethanol

ethyl(±)-4-(2-fluorophenyl)-1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carboxylate(2.c); mp 148°-150° C., recrystallized from n-hexane

ethyl(±)-1,4-dihydro-5-methoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate(2.d); mp 118°-120° C., recrystallized from n-hexane

methyl(±)-4-(3-chloro-2-fluorophenyl)-1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carboxylate(2.e); mp 214°-216° C., recrystallized from diisopropyl ether/methanol

methyl(±)-4-(2-bromophenyl)-1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carboxylate(2.f); mp 204°-205° C., recrystallized from diisopropyl ether/methanol

(±)-1,4-dihydro-5-methoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid(2-dimethylaminoethyl)ester (2.g); mp 137°-138° C. from ethylacetate

EXAMPLE 3(±)-1,4-Dihydro-5-isopropoxy-2-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid

Three g (6.2 mMol) benzyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylateare hydrogenated at normal pressure and at ambient temperature with theuse of 1.5 g 10% palladium on active charcoal in 100 ml ethanol. Thetake up of hydrogen is finished after 30 minutes. The catalyst isfiltered off, the solvent is distilled off in a vacuum and thecolorless, crystalline residue is recrystallized from diisopropylether/ethyl acetate. There is obtained(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid in the form of colorless crystals with a melting point of 164°-166°C. (decomp.).

The benzyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylateused as starting material is prepared analogously to Example 1 with theuse of dibenzyl1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate.

Obtained in an analogous manner is(±)-1,4-dihydro-5-methoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylicacid-(2-dimethylaminoethyl)-ester (3.a); mp 137°-138° C. from ethylacetate.

EXAMPLE 4 Ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate

1.3 g (43 mMol) sodium hydride (80% in paraffin oil) are suspended in200 ml dry dimethylformamide and 12.5 g (33 mMol) ethyl(±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylateis added in portions thereto at ambient temperature, while stirring.After cessation of the evolution of gas, the reaction mixture is furtherstirred for 15 minutes at ambient temperature. 7.2 g (43 mMol) isopropyliodide is then added. Stirring is continued for three days at ambienttemperature. The solvent is evaporated off in vacuo and after adding of500 ml water the residue is treated in the ultrasonic bath for 30minutes. The resulting crystalline mass is filtered off and dried at 50°C.

For purification of the crude product, it is dissolved in ethyl acetateand chromatographed over silica gel with toluene/ethyl acetate (3:1v/v). The solvent of the fractions of Rf 0,4 is evaporated in vacuo andthe residue is stirred till crystallization with n-hexane. The productis filtered off and recrystallized from 60 ml n-hexane. Colorlesscrystals are obtained, mp 102°-103° C.

The ethyl(±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylateused as starting material is prepared as follows:

A solution of 79.2 g (0.2 mol) diethyl1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridin-3,5-dicarboxylatein 400 ml dimethylformamide is added dropwise, under an atmosphere ofnitrogen, to a suspension of 6.0 g (0.2 mol) sodium hydride (80% inparaffin oil) in 100 ml dry dimethylformamide. Upon slowing down of theevolution of gas, the reaction mixture is further stirred for tenminutes at ambient temperature and subsequently 16.2 g (0.2 mol)s-triazine in 300 ml dimethylformamide are added dropwise thereto. Thereaction mixture is heated to 110° C. for 16 hours under stirring and,after cooling, evaporated in a vacuum. The residue is stirred with 1.5 lacetone, filtered and the filtrate evaporated in a vacuum. The residueis chromatographed over silica gel with dichloromethane/methanol (9:1v/v). The fraction with Rf 0.45 is stirred with 200 ml chloroform thepale beige crystals are filtered off. For further purification they arerecrystallized from ethanol and colorless crystals are obtained, mp 261°C.

The diethyl1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridin-3,5-dicarboxylateused as starting material is prepared as follows:

Fifty g (0.29 mol) 2-trifluoromethyl benzaldehyde and 76 g (0.58 mol)ethyl acetoacetate in 30 ml aqueous ammonia are boiled for 16 hours with200 ml ethanol. The product, precipitated after cooling, is filtered offand washed with cold ethanol. Pale beige crystals are obtained, mp142°-143° C.

The following comparative experiments demonstrate the pharmacologicallyeffectiveness of the compounds of general formula (I)':

(a) Isolated smooth muscle

Isolated smooth muscle from rabbits (blood vessel rings, A. basilaris,A. coronaria, A. saphena) are fixed in an organ bath in such a mannerthat isometric contractions can be measured. The contraction isinitiated by a potassium depolarization in tyrode solution. Theexperimental protocol is a known standard model for the recognition ofcompounds which block the calcium canals opened in the potassiumdepolarization (Fleckenstein, 1983). As can be seen from the followingTable 1, some substances act semi-maximally relaxingly in the nanomolarrange. In part, this potency considerably exceeded that of the alreadyknown calcium antagonists diltiazem and nifedipine.

(b) Isolated papillary muscle

Papillary muscle from the left ventricle of the guinea pig is fixed, asin the case of isolated vessels, in an organ bath for isometriccontraction measurement and electrically stimulated by field stimulationwith a frequency of 250/min (stimulation period 10 msec, amplitudesupramaximal). The following Table 2 shows that the compounds displaytheir calcium antagonist action selectively on the smooth vessel muscleand on the myocardium show surprisingly, in the therapeutic range (1-100nmolar) no negative but in part even positive inotropic action. However,it cannot be excluded that the dimethyl sulfoxide used as a solvent hascontributed to the observed positive inotropic action. The compound ofExample 1(c) possess, at a therapeutic concentration of 3×10⁻⁷mol/liter, a maximum increase of the contractility of 36% and at aconcentration of 4×10⁻⁹ mol/liter, this is +18%.

                  TABLE 1                                                         ______________________________________                                        Table 1 shows concentrations (IC.sub.50, mol/l) of                            compounds (I) which bring about a semi-maximum                                inhibition of the K+ depolarization contraction of                            blood vessel rings in an organ bath. For comparison,                          there is given the IC.sub.50 values of the calcium                            antagonists diltiazem and nifedipine.                                         Compound of                                                                   Example No.                                                                            A. bas..sup.1                                                                              A. cor..sup.2                                                                             A. saph..sup.3                              ______________________________________                                        1          5 × 10.sup.-9                                                                       3 × 10.sup.-8                                                                     7 × 10.sup.-9                          1a       2.4 × 10.sup.-9                                                                     2.7 × 10.sup.-9                                                                     8 × 10.sup.-9                          1h         3 × 10.sup.-6                                                                     1.5 × 10.sup.-8                                                                     1 × 10.sup.-6                          1b       .sup. 6.6 × 10.sup.-10                                                              .sup. 7.5 × 11.sup.-10                                                              3.4 × 10.sup.-9                        1c       1.5 × 10.sup.-8                                                                     6.5 × 10.sup.-8                                                                     1 × 10.sup.-6                          1g       5.9 × 10.sup.-9                                                                     3.2 × 10.sup.-9                                                                     --                                           1l       7.4 × 10.sup.-9                                                                     3.1 × 10.sup.-8                                                                     3.9 × 10.sup.-7                        1p       1.6 × 10.sup.-8                                                                     5.3 × 10.sup.-8                                                                     --                                           1q       3.5 × 10.sup.-8                                                                     1.9 × 10.sup.-7                                                                     --                                           2        2.5 × 10.sup.-7                                                                       1 × 10.sup.-6                                                                     9 × 10.sup.-8                          2a         6 × 10.sup.-9                                                                       1 × 10.sup.-8                                                                     6 × 10.sup.-7                          2b       1.8 × 10.sup.-9                                                                     1.2 × 10.sup.-8                                                                     6 × 10.sup.-7                          diltiazem                                                                              1.2 × 10.sup.-7                                                                     1.7 × 10.sup.-7                                                                     2.9 × 10.sup.-6                        nifedipine                                                                             2.7 × 10.sup.-9                                                                       5 × 10.sup.-9                                                                     5.9 × 10.sup.-8                        ______________________________________                                        .sup.1 A. bas. = arteria basilaris                                                                 obtained from                                            .sup.2 A. cor. = arteria coronaria                                                                 rabbits; average                                         .sup.3 A. saph. = arteria saphena                                                                  diameter 0.5-1.0 mm                                  

                  TABLE 2                                                         ______________________________________                                        Changes of the contraction amplitude of isolated                              papillary muscle of the guinea pig (stimulation                               frequency 250/min, stimulation time 10 msec,                                  stimulation amplitude 10-20 V field stimulation).                             IC = inhibition concentration, IC.sub.100 corresponds to                      maximum action. Δ% = maximum decrease of the                            contractility. The inhibiting concentrations of                               diltiazem and nifedipine are given for comparison.                            Compound of                                                                              Number of                                                          Example No.                                                                              Animals       IC.sub.50 /100                                                                         Δ%                                    ______________________________________                                        1          (n = 7)       3.10.sup.-4                                                                            -40                                         1a         (n = 4)       3.10.sup.-4                                                                            -48                                         1h                       1.10.sup.-4                                                                            -38                                         1l                       1.2.10.sup.-4                                                                          -38                                         1p                       1.10.sup.-5                                                                            -23                                         1q                       1.10.sup.-5                                                                             -7                                         1h         (n = 4)       3.10.sup.-4                                                                            -54                                         diltiazem  (n = 6)       10.sup.-5                                                                              -60                                         nifedipine*              10.sup.-6                                                                              -80                                         ______________________________________                                         *Hof and Scholtysik, J. Cardiovasc. Pharmacol. 5:176-183, 1983),              Experiments on the papillary muscle of the rabbit.                       

Table 2 shows the maximum actions on the contractility in the case ofthe concentration necessary herefor (IC₁₀₀ =inhibitory concentration).From this, it can be seen that the comparison compounds, even in thecase of considerably lower concentrations (IC₁₀₀), show a higherdecrease of the contractility. The concentration IC₁₀₀ lies far outsideof the therapeutic range of the compounds according to the presentinvention so that a negative inotropism is there not to be found. Itfollows from this that the therapeutic safety of the compounds accordingto the present invention is considerably increased in comparison withthe prior art.

We claim:
 1. A compound selected from the group consisting of:ethyl(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate,[2-(N,N-diethylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(4-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-pyridyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-5-ethoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-2-methyl-5-propoxy-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-cyanophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate,(2-phenoxyethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-methoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,methyl(±)-4-(2,6-dichlorophenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate,(2-phenoxyethyl)-(±)-1,4-dihydro-5-isobutoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,(2-phenoxyethyl)-4-(2-difluoromethoxyphenyl)-1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylate,benzyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate,cyclopropylmethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,ethyl(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate,(trans-cinnamyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydro-5-isobutoxy-2-methyl-1,6-naphthyridine-3-carboxylate,(N-benzyl-3-pyrrolidinylmethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylate,ethyl(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl-1,6-naphthyridine-3-carboxylate,[2-(N-benzyl-N-methylamino)ethyl]-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,[2-N-benzyl-N-methylamino)ethyl]-(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate,and(2-trimethylammonioethyl)-(±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(3-nitrophenyl)-1,6-naphthyridine-3-carboxylateiodide, or a pharmacologically acceptable salt thereof.
 2. Apharmaceutical composition for treating blood vessel diseases comprisingan effective amount of a compound according to claim 1 in admixture witha solid or liquid pharmaceutical diluent or carrier.
 3. A method fortreating diseases of blood vessels which comprises treating a hostsuffering therefrom with a pharmaceutical composition according to claim2 in unit dosage form.